Summary The objective of the proposed research is to better understand the underlying neurophysiology of cerebral/cortical visual impairment (CVI), the leading cause of congenital vision loss in the United States and developed world. CVI is associated with peri-natal damage to visual cerebral structures and pathways, and leads to a myriad of impairments in visual function. Despite this alarming public health issue, there is a fundamental gap in our understanding as to how the visual system develops in the setting of cerebral compared to ocular based visual impairment. Current studies using standard clinical imaging modalities are limited in their ability to characterize brain functional reorganization in the setting of widespread neurological injury. To further advance our understanding, we will employ multi-modal neuroimaging to characterize whole brain as well as regional structural and functional brain connectivity in CVI associated with periventricular leukomalacia (PVL). In our first aim, we will characterize white matter integrity and structural connectivity using high angular resolution diffusion imaging (HARDI). In our second aim, we will characterize functional brain connectivity networks using resting state functional connectivity (rsfc)MRI. Using a graph theoretical analysis framework, we will then investigate network topological properties and the coupling between structural and functional networks. Further characterization of functional connectivity will be carried out using stepwise functional connectivity (SFC) analysis. This complementary approach allows for the investigation of widespread network alterations on information transfer across the entire brain, and represents a key distinguishing innovation of this proposal. Specifically, the examination of topological characteristics and the nature of structural-functional network coupling will lead to a better understanding of CVI by uncovering the nature of network alterations in the setting of congenital brain injury and how it relates to visual function. Findings will be compared to ocular visually impaired (OVI) individuals (matched for residual visual function) as well as neurotypical sighted controls. Our overarching hypothesis is that CVI is associated with key differences in the organization and relationship between structural-functional connectivity networks. Furthermore, we predict that in CVI, functional networks responsible for visual processing will show evidence of reorganization in response to large-scale white matter injury, and this may serve as a useful biomarker in relation to clinical functional assessments. This study will provide a high level of insight that has not been previously achieved by previous investigations relying on standard clinical imaging approaches. Uncovering how the brain develops in the case of CVI and how it differs from ocular based visual impairment is a crucial first step in developing a neurorehabilitative framework specifically designed for the care of children with this condition. This is of great significance for individuals with CVI; a population that has been immensely underserved despite its important